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Oncology Boards > Pecorino > Flashcards

Pecorino Flashcards

1
Q

Hallmarks of cancer

A
  1. Capability for autonomous growth signals 2. Evasion of growth inhibitory singals 3. Evasion of apoptotic cell death 4. Unlimited replicative potential 5. Angiogenesis 6. Invasion and metastasis
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2
Q

Enabling characteristics of cancer

A

Crucial for acquiring the six hallmarks of cancer 1. Genome instability 2. Tumor promoting inflammation

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3
Q

Emerging hallmarks of cancer

A
  1. Reprogramming energy metabolism 2. Avoiding immune destruction
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4
Q

Oncogenes - dominant or recessive

A

Dominant - mutation in only one allele sufficient for an effect

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5
Q

Tumor suppressor genes - dominant or recessive

A

Recessive - one intact allele generally enough to inhibit growth - Supports “two hit” hypothesis of carcinogenesis

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6
Q

Haploinsufficiency

A

Idea that rather than tumor suppressor genes being recessive, only one mutated allele may be enough to induce cancer phenotype - Normal allele produces 1/2 the normal protein product which is not enough to suppress tumor formation

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7
Q

Ras function

A

intracellular transducer protein - acts subsequently to binding of a growth factor to its receptor - Involved in transmitting the signal from the receptor through the cell

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8
Q

Ras is a ___ protein

A

G protein - activated by exchange of GDP to GTP

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9
Q

p53 normal role

A

Coordinates responses of the cell (cell cycle arrest, DNA repair, apoptosis) to different types of stress (DNA damage, hypoxia)

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10
Q

p53 is a ___ and acts as a ___

A
  • Tumor suppressor gene - Acts as a transcription factor - induces expression of genes required to carry out its function
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11
Q

retinoblastoma gene (Rb) is a

A

Tumor suppressor gene

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12
Q

Rb function

A

Central role in regulating the cell cycle - Inhibits cell proliferation by binding to and suppressing an essential transcription factor of cell cycle progression

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13
Q

Rb activity regulated by

A

Phosphorylation by cyclin D and the cyclin-dependent kinases (4/6)

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14
Q

Small localized areas of hypermutation

A

Kataegis

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15
Q

One-off cell crisis that shatters chromosomes and result in 10-100’s of genomic rearrangements

A

Chromothripsis

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16
Q

Transitions and transversions are what type of mutation?

A

Base substitutions

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17
Q

Transitions substitute a ___ for a ___

A

Purine/Purine

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18
Q

Transversions substitute ___ for ___

A

Purine/Pyrimidine

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19
Q

What is “wobble” and “deceneracy” in the genetic code?

A

3rd nucleotide of a codon may be changed and new codon may code for same amino acid

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20
Q

Alpha particles are made of

A

2 protons and 2 neutrons

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21
Q

Beta particles are made of

A

electrons

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22
Q

X-rays are ___ radiation vs alpha particles that are ___ radiation

A
  1. low-linear energy transfer (LET) 2. high-LET
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23
Q

___-LET radiation more commonly causes DSBs and lead to chromosomal translocations and deletions

A

High

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24
Q

Ionizing radiation therapy includes

A
  • alpha and beta particles - gamma rays
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25
Q

How does ionizing radiation cause DNA damage?

A
  1. Indirect - interacts with atoms, ejects e-, causes an ion to form, interacts with water (radiolysis) –> ROS 2. DNA directly ionized
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26
Q

What are the 3 ROS formed by ionizing radiation therapy

A

Hyroxyl (OH) Hydrogen peroxide (H2O2) Superoxide (O2-)

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27
Q

Which type of UV radiation is the most effective carcinogen?

A

UVB`

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28
Q

___ are responsible for the majority of UVB induced mutations

A

Cyclobutane pyrimidine dimers

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29
Q

UVA ___damages DNA via___

A
  • Indirectly - Free-radical mediated damage
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30
Q

___ transversions are characteristic of UVA damage

A

G-T

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31
Q

Common MOA of chemical carcinogens

A

Electrophilic (electron-deficient) form reacts with nucleophilic sites (donate electrons) in purine and pyrimidine rings of nucleic acids

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32
Q

Example of polycyclic aromatic hydrocarbons (PAH)

A

Benzo(a)pyrene - major well-known carcinogen in cigarettes

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33
Q

Heterocyclic amines are

A

carcinogens produced by cooking meat

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34
Q

One-step DNA repair

A
  • Direct reversal of DNA damage - Removal of alkyl group from the O6 atom of guanine after exposure of DNA to alkylating carcinogens
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35
Q

What DNA repair enzyme is involved in one-step DNA repair?

A

Alkyltransferase

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36
Q

What type of DNA damage does NER repair

A

Helix-distorting lesions - bulky DNA adducts induced by environmental agents (UVV, PAHs)

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37
Q

Two subpathways of NER

A
  1. Global genome NER (for helix distortion) 2. Transcription-coupled repair (damage interfering with transcription)
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38
Q

Describe the process of repair by NER

A
  1. Lesion + adjacent nucleotide excised by endonucleases 2. DNA polymerase delta/epsilon fills gap with opposite strand as template (proliferating cell nuclear factor is part of polymerase holoenzyme and physically forms ring that encircles and binds the damaged region
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39
Q

What DNA polymerase is used in NER

A

delta(δ )/epsilon(ε)

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40
Q

What does NER stand for?

A

Nucleotide excision repair

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41
Q

What genetic disease is characterized by a defect in NER?

A

Xeroderma pigmentosum (XP)

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42
Q

What does BER stand for?

A

Base excision repair

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43
Q

What does BER repair?

A

Targets chemically altered bases induced primarily by endogenous mechanisms - w/o BER, would cause a point mutation

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44
Q

Describe the steps of BER

A
  • DNA damage-specific glycosylases (OGG1 and MUTYH) scan bases for 8-oxoguanine lesions - Lesion is flipped out of the helix and cleaved –> abasic site - Endonuclease cleaves DNA strand at abasic site - DNA polymerase β replaces nucleotide, ligase fills gap
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45
Q

What does PARP stand for?

A

poly(ADP-ribose) polymerase

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46
Q

What role does PARP play in BER

A

Interacts with single strand break intermediates formed during BER –> poly(ADP-ribose) chains –> signals to other DNA repair proteins and leads to modification of histones –> relaxed chromatin structure for increased DNA accessibility

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47
Q

What type of DNA damage does mismatch repair fix

A

Replication errors that have escaped editing by polymerases - includes repair of insertions and deletions produced as a result of slippage during repair of repetitive sequences and nucleotide mismatches

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48
Q

Describe the steps in mismatch repair

A
  1. mismatch recognized by hMSH2/6 and hMSH2/3 2. hMLH1/hPMS2 and hMHL1/hPMS1 recruited 3. Endonucleases and exonucleases removed nucleotides around and including the mismatch DNA polymerases resynthesizes a newly replicated strand
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49
Q

What human cancer syndrome commonly has loss of mismatch repair

A

Hereditary non-polyposis colorectal cancer

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50
Q

What are the two types of recombinational DNA repair

A

Homologous repair and non-homologous end-joining

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51
Q

What type of DNA damage does recombinational repair fix

A

double-strand DNA breaks

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52
Q

What does homologous recombination require

A

The presence of sister chromatids formed during DNA synthesis - template for recombining severed ends

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53
Q

What kinase is activated by DSBs in HR?

A

ataxia telangiectasia mutated (ATM) kinase

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54
Q

What substrate does ATM act on

A

RAD50/MRE11/NBS1 complex –> 5’-3’ exonuclease activity creates 3’ DNA ends

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55
Q

What aids in nuclear transport of RAD51

A

BRCA1/2

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56
Q

What does RAD51 do in HR

A

Binds to exposed 3’ ends (facilitated by RAD52) –> exchanges a homologous sequence from a single strand w/in a double stranded molecule (i.e. sister chromatid)

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57
Q

Junctions formed as a result of HR

A

Holliday junctions

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58
Q

Which form of recombinational repair is error prone and which is very unlikely to form errors?

A
  1. Error prone = non-homologous end-joining 2. Rare errors = homologous recombination
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59
Q

What inherited disease causes defective HR and makes patients sensitive to x-rays?

A

Ataxia telangiectasia - mutation in ATM kinase

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60
Q

Clinically used antimetabolites

A

Methotrexate, 5-fluorourail (5-FU)

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61
Q

5-FU MOA

A

Antimetabolite Derivative of uracil -> converted to fluorodeoxyuridylate (F-dUMP) - competes with natural substrate dUMP for catalytic site of thymidylate synthase (inactivates) –> depletes dTMP and dTTP –> dUMP and dUTP accumulate –> DNA synthesis in rapidly dividing cells compromised

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62
Q

F-dUMP competes with ___ for catalytic site of _____

A

dUMP thymidylate synthase

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63
Q

Thymidylate synthase produces

A

deoxythymidylate (dTMP)

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64
Q

Methotrexate MOA

A

Antimetabolite Competitive inhibitor of dihydrofolate reductase

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65
Q

What does dihydrofolate reductase do?

A

Regenerates tetrahydrofolate which produces N5N10 methylenetetrahydrofolate that is required in thymidylate synthase reaction

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66
Q

Vincristine and Vinblastine bind to ____ and do what?

A

Tubulin Prevent microtubule assembly

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67
Q

Paclitaxel binds to ___ and does what?

A

Beta-tubulin subunit in polymers Stabilizes microtubules against depolymerization

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68
Q

What can assist in making radiation-induced damage permanent?

A

Oxygen Also, more DS breaks occur in cells irradiated in presence of oxygen than in those without

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69
Q

Mechanisms of chemotherapy resistance

A

Increasing drug efflux Decreasing intake of drug Increasing the number of target molecules within the cell Altering drug metabolism or DNA repair processes

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70
Q

MDR codes for ____?

A

P-glycoprotein (P-gp)

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71
Q

P-glycoprotein is____ and its MOA is ____

A

Chloride ion efflux pump ATP hydrolyzed –> conformational change of P-gp–> drug released extracellularly

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72
Q

PARP inhibitors are used in tumors with ____ mutations

A

BRCA1/2

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73
Q

Inhibition of PARP causes impaired…

A

base excision repair and the accumulation of SS DNA breaks that can lead to DS breaks (normally repaired by homologous recombination pathways

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74
Q

BRCA1 or BRCA2 mutations cause deficiency in…

A

homologous recombination and DS repair

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75
Q

Four common types of DNA-binding domains

A

helix-turn-helix motif Leucine zipper helix-loop-helix motif zinc finger motif

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76
Q

T/F: misregulation of a single transcription factor can cause cancer

A

T

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77
Q

AP-1 transcription factor is important in

A

Processes of growth, differentiation and death –> therefore plays a role in carcinogenesis

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78
Q

AP-1 binds:

A

12-O-tetradecanoylphorbol-13-acetate (TPA) response element or cAMP response element

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79
Q

AP-1 transcription factor is composed of ___ components and can be produced by dimers of proteins from the ___ and ____ families

A

two; Jun and Fos

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80
Q

Jun acts as __1__ of proliferation, Jun B acts as a __2__ in the presence of __3__

A
  1. Positive regulator of proliferation 2. Negative regulator 3. Jun
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81
Q

Where in the cell do steroid hormones work?

A

Pass through cell membrane, bind intracellular receptors in cytoplasm

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82
Q

What makes up the histone core?

A

Two copies of histones H2A, H2B H3 and H4

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83
Q

What are the two main types of epigenetic mechanisms

A
  1. Histone modifications
  2. DNA methylation
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84
Q

What are the main post-translational modifications that can happen to histones?

A

Acetylation

Methylation

Phosphorylation

Ubiquination

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85
Q

What are the two families of enzymes that participated in acetylation of histones?

A

Histone acetyltransferases (HATs - add acetyl)

Histone deacetylases (HDACs - remove acetyl)

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86
Q

What does histone acetylation do?

A

Neutralizes positive charge on lysine residues –> relaxes chronmatin –> more transcription

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87
Q

What does histone deacetylation do?

A

Restores positive charge to lysine in histone tails –> compacted chromatin –> less transcription

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88
Q

What tumor suppressor gene works in part through acetyl modification of histones? Which enzyme does it recruit to do this?

A

RB

HDACs

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89
Q

Where does DNA methylation occur?

A

Position 5 of cytosine only at cytosine nucleotides that are situated 5’ to guanine nucleotides (CpGs)

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90
Q

Where are CpG isloands commonly located? What is their methylation status?

A

Promoter region of genes

Usually non methylated –> transcription can occur

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91
Q

What enzymes mediate DNA methylation?

A

DNA methyltransferases (DNMTs)

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92
Q

Are DNA methylation patterns inheritable?

A

Yesh.

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93
Q

Areas of chromatin that are relaxed are indicative of ___ and are associated with ____ mutation density.

A

active transcription

low

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94
Q

DNA hypo/hyper methylation has been observed in normally unmethylated/methylated CpG islands of gene promoters in cancer

A

hypermethylated

unmethylated

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95
Q

Gene silencing by ____ may be an important mechanism of carcinogenesis by which critical genes such as ____ are turned off

A

Methylation

Tumor Suppressor

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96
Q

Key genes affected by DNA methylation in cancer

A

Rb

p16INK4a (inhibits cell cycle)

pro-apoptotic death-associated protein kinase (DAPK)

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97
Q

What is a non-genotoxic carcinogen?

A

Agents that do not mutate genes but are rather epigenetic carcinogens

ex: phenobarbital in mice

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98
Q

Is the genome of a cancer cell generally hypo or hypermethylated?

A

Overall HYPOmethylated

Hypermethylation in specific gene promoters

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99
Q

What are microRNAs (miRNA) and what do they do?

A

small, non-protein coding RNAs

Regulate the expression of mRNA - powerful regulators of gene expression (repress genes)

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100
Q

What are telomeres composed of?

A

TTAGGG sequences bound by shelterin complex

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101
Q

What does telomerase do?

A

Maintains telomere length in certain cell types

Reverse transcriptase that has complementary base pairs to the TTAGG repeats in telomeres

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102
Q

Maintenance of ___ important for cancer cell immortality and tumor growth which is commonly accomplished by upregulating ____

A

Telomeres

Telomerase

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103
Q

What drugs are used to target DNA methyltransferases and what do they do?

A

5-azacytidine (5-azaC), 5-aza-2’-deoxycytidine

Bind DNA methyltransferases –> significant demethylation

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104
Q

What are the four types of proteins involved in transduction of a growth factor signal

A

growth factors

growth factor receptors

intracellular signal transducers

nuclear transcription factors

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105
Q

Many growth factors are

A

tyrosine kinases

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106
Q

What are EGF receptors also called?

A

ErbB or HER (1-4)

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107
Q

What is unique about HER2 compared to other EGFRs

A

HER2 doesn’t bind to a ligand but is a co-receptors for other EGFRs; other EGFRs are receptor tyrosine kinases

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108
Q

What are the six steps of EGF signalling

A
  1. Binding of growth factor to receptor
  2. Receptor dimerization
  3. Autophosphorylation
  4. Activation of intracellular transducers - includes RAS
  5. Activation of a cascade of serine/threonine kinases (Raf, MEK, MAPK)
  6. Regulation of transcription factors for gene expression
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109
Q

What does dimerization of EGFRs cause

A

Changes shape of receptor allowing access of ATP and substrate to the catalytic kinase domain –> autophosphorylation from on dimer to the other

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110
Q

What activates RAS

A

Son of Sevenless (SOS)

Src homology (SH2 and SH3) domains on Grb2 recognize phosphyorylated EGFR –> interact with son of sevenless (SOS) –> activates RAS

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111
Q

What kind of molecule is RAS

A

GTP-binding protein

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112
Q

GTP-binding proteins are inactive when they are bound to ____ and active when bound to ____

A

GDP

GTP

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113
Q

What does son of sevenless (SOS) do?

A

Activates RAS by mediating exchage of GDP to GTP

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114
Q

What is farnesylation

A

Addition of C15 farnesyl isoprenoid lipid to RAS and is required for localizing RAS to the cell membrane

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115
Q

What does activated RAS (RAS-GTP) bind to

A

Raf

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116
Q

What kind of molecule is Raf?

A

Serine/threonine kinase

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117
Q

Raf is one of the main effectors of

A

RAS

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118
Q

Raf phosphorylates what?

A

mitogen-activated protein kinase kinase (MAPKK or MEK)

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119
Q

What kind of molecule is MAPKK

A

Dual tyrosine and serine/threonine kinase

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120
Q

What does activated MAPPKK (MEK) do?

A

Phosphorylates mitogen-activated protein kinases (MAPKs, aka ERKs)

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121
Q

What do MAPKs do

A

Provide cytoplasmic link between activated RAS on plasma membrane and regulation of gene expression because MAPKs can enter the nucleus

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122
Q

What is AP-1

A

Transcription factor - binds DNA and regulates expression of genes involved in growth, differentiation and death

Target of MAPK cascade

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123
Q

What does AP-1 bind to

A

cyclin D gene - critical regulator of the cell cycle

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124
Q

What gene families make up AP-1

A

jun and fos

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125
Q

What are the Myc family of molecules

A

Transcription factors - Myc, Max, Mad, Mxi

Targets of MAPK

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126
Q

What are some of the gene targets of Myc?

A

N-Ras, p53

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127
Q

What is phosphatidylinositol 3-kinase (PI3K)

A

Lipid kinase, effector protein downstream of RAS

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128
Q

Interaction of RAS with PI3K results in production of

A

a second messenger, PIP3

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129
Q

What does PIP3 recruite and what kind of molecule is it?

A

PDK-1

serine/threonine kinase

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130
Q

What does PDK-1 do

A

phosphorylates Akt

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131
Q

What is Akt and what does it do?

A

serine/threonine kinase

anti-apoptotic and survival roles by phosphorylating distinct target proteins; ex: m-TOR

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132
Q

What is SRC?

A

Intracellular tyrosine kinase

Roles in cell proliferation, regulation of cell adhesion, invasion and motility

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133
Q

What can activate SRC? What does activated SRC do?

A

EGF receptor; focal adhesion kinase (FAK)

Activation of SRC leads to disassembly of focal adhesions –> increased cell motility

Inhibits E-cadherin (important for cell invasion)

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134
Q

Oncogenes are dominant or recessive?

A

Dominant

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135
Q

PDGF can act as a oncogene or tumor suppressor gene?

A

Oncogene - aberrant location in cytoplasm instead of secreted

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136
Q

what does the oncogene v-erbB do?

A

Makes mutated EGFR that triggers cell division w/o EGF binding

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137
Q

RAS as an oncogene

A

Loss of GTPase activity of RAS protein –> constiutive activation of RAS

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138
Q

Most commonly mutated form of B-Raf? What does it do?

A

V600E

Causes constitutive kinase activity and insensitivity to feedback mechanisms –> abnormal cell growth

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139
Q

How does BCR-ABL work as an oncogene

A

Fusion protein BCR-ABL maintained in cytoplasm –> nuclear kinase constitutively activated where it shouldn’t be and interferes with normal signal transduction pathways

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140
Q

How does Imatinib (Gleevec) work?

A

Binds ATP-binding pcoket w/in catalytic domain –> preferential binding to inactive state of kinases

Works against PDGFR, ABL and c-Kit

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141
Q

Four stages of the cell cycle

A
  1. G1
  2. S phase
  3. G2
  4. M phase
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142
Q

What stages make up interphase

A

G1, S, G2

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143
Q

What is G0

A

G0 = quiescent state, outside cell cycle

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144
Q

Passage through the different phases of the cell cycle is regulated by

A

Cyclins and cyclin-dependent kinases

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145
Q

When cyclins bind to cdks, they ___ the cdk

A

activate

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146
Q

Which cyclins drive progression through G1

A

Cyclin D + cdk 4/6

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147
Q

What does cyclin D do?

A

regulates expression of cyclin E gene (product is important for G1 to S transition)

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148
Q

at cyclin-cdk is important for S phase progression

A

Cyclin A-cdk2

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149
Q

What cyclin-cdk directs G2 and the G2 to M phase transition

A

Cyclins A, B-cdk1

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150
Q

G1 check point leads to cell cycle arresnt in response to what?

A

DNA damage - ensures DNA isn’t replicated in S phase

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151
Q

The G2 checkpoint leads to arrest of the cell cycle in response to what

A

Damaged and/or unreplicated DNA - ensures proper completion of S phase

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152
Q

M checkpoint leads to arrest of chromosomal segregation in response to what

A

misalignment of the mitotic spindle

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153
Q

How to cyclins/cdks exert their effects

A

Phosphorylating target proteins

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154
Q

What two processes predominantly control cell cycle progression?

A
  1. protein phosphorylation and dephosphorylation by kinases and phosphatases
  2. Specific proteolytic degradation targeted by the addtion of ubiquitin to the proteasome
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155
Q

cdks are what type of kinase

A

serine/threonine

156
Q

What are the four ways cdks are regulated

A
  1. association with cyclins (activates)
  2. Associateion with cdk inhibitors
  3. addition of phosphate groups that activate cdk activity
  4. addition of phosphate groups that inhibit cdk activity
157
Q

What does upiquitin do?

A

Targets protei for degradation by the proteasome

158
Q

What enzyme catalyzes transfer of ubiquitin to target protein?

A

ubiquitin-protein ligase

159
Q

What two families of inhibitors are involved in regulating cyclin-cdk activity?

A

p16ink4a (INK) family

p21 (Cip/Kip) family

160
Q

What makes up the INK family of proteins

A

p16ink4a, p15ink4b, p18ink4c, p19ink4d

Bind cdks 4/6 and interfere with cdks 4/6 ability to bind cyclin D

161
Q

What are the members of the p21 proteins and what do they do?

A

p21cip1, p27kip1, p57kip2

Inhibitors that interact with both cyclis and their associated cdks (mainly cdk2 and cycline E) and block the ATP-binding site –> disables kinase activity

162
Q

What two steps are needed for cdks to become active?

A
  1. dephosphorylation of the inhibitory phosphate groups by cdc25 phosphatases
  2. phosphorylation of a central threonine residue Thr161, by cdk-activating kinase (CAK)
163
Q

What is the molecular link for the G1-S phase transition?

A

RB protein (tumor suppressor protein)

164
Q

RB is a tumor suppressor or oncogene?

A

Tumor suppressor

165
Q

What does RB regulate

A

Activity of E2F transcription factor family - physically interferes with the transactivation domain of E2Fs

166
Q

What two main effector proteins bind to RB

A

HDAC and E2F transcription factor

167
Q

What regulates the interactions b/w RB, E2F and HDACS?

A

serine/threonine phosphorylation by cyclin D and E families

168
Q

In the absence of a growth signal, RB is in a _____ state and is bound to _____

A

hypophosphyorylated; E2F and HDAC

169
Q

How is RB phosphorylated?

A
  1. cyclin D-cdk4 phosphorylates RB when stimulated by growth factors –> conformational change –> releases HDAC
  2. Cyclin E gene is expressed when HDAC released from RB –> cyclin E-cdk2 phosphorylates RB (Ser567) –> release of E2F
170
Q

What genes are expressed when E2F is released from RB?

A

cyclin A, thymidylate synthase, dihydrofolate reductase (important for S phase)

171
Q

What does the G2 check point do?

A

Blocks entry into M phase for cells with DNA damage or that have not correctly completed S phase

172
Q

What does DNA damage activate in the G2 checkpoint?

A

ATR or ATM

173
Q

What do ATR and ATM do in the G2 checkpoint?

A

Activated by DNA damage

ATR phsophorylates Chk1

ATM phosphorylates Ch2

174
Q

Other than ATR, what else is needed for full Chk1 activation

A

claspin (mediator protein)

175
Q

What does Chk1 target?

A

Cdc25

176
Q

What does Cdc25 do?

A

Tyrosine phosphatase; regulates cdk activity by removing inhibitory proteins –> activates cdks

177
Q

What does inhibition of Cdc25 by Chk1 do and when does this happen?

A

Happens during G2 checkpoint

Blcoks removal of inhibitory phosphate on cdk –> prevents mitosis

178
Q

Activation of the G2 checkpoint activates ____ and inhibits ____

A

Chk1; Cdc25

179
Q

What is Plk1 and what does it do?

A

Protein that targets claspin and Wee1 for degradation, directly inhibits Chk2; causes re-entry into cell cycle (check point recovery) in G2

180
Q

What do unattache chromatid pairs recruit?

A

Inhibitors of the anaphase-promoting complex (this is a upiquitin-protein ligase that starts anaphase)

181
Q

What are Aurora kinases

A

serine/threonine kinases

182
Q

What do the Aurora kinases do?

A

Regulate mitosis - chromosome segregation and the spindle checkpoint

183
Q

Where does Aurora kinase A localize?

A

Centromeres during interphase; spindle poles and spindle microtubules at beginning of mitosis

184
Q

Where does aurora kinase B localize and when is it highest in activity

A

Location: first centrometeres, then middle of spindle to between dividing cells

Most active later in mitosis that A

185
Q

Where does aurora kinase C localize and when is it highest activity

A

spindle poles; active during late mitosis

186
Q

What is Knudson’s two-hit hypothesis

A

The strict definition of a tumor suppressor gene is a gene in which a germline mutation predisposes an individual to cancer

187
Q

BRCA1 and 2 are tumor suppressor genes or oncogenes?

A

Tumor suppressor

188
Q

What is the primary function of BRCA2?

A

Recruitment of recombinase RAD51 to double strand DNA breaks

189
Q

What is the function of BRCA1

A

Roles in homologous recombination including recruitment of RAD51

190
Q

Mutations in BRCA genes can lead do defective ___ that destablizes the genome leading to ____ and _____

A

homologous recombination; chromosomal rearrangements; mutation

191
Q

Most phosphatases are tumor suppressors or oncogenes?

A

Tumor suppressors

192
Q

PTEN is an oncogene or a tumor suppressor gene?

A

Tumor suppressor

193
Q

PTEN is what kind of molecule?

A

Phosphatase with dual specificity - lipid and protein

194
Q

What does PTEN do?

A

Dephosphorylates PIP3 to form PIP2 –> antagonizes PI3K activity

195
Q

What is the net result of loss of function of PTEN

A

Loss of inhibitory dephosphorylation –> constitutively active PI3K –> activtes AKT and mTOR –> induces cell proliferation and inhibits apoptosis

196
Q

What is an example of a kinase that is not oncogenic?

A

ATM

197
Q

Retinoblastoma is an oncogene or a tumor suppressor gene?

A

Tumor suppressor

198
Q

What kind of molecule is retinoblastoma

A

multi-functional protein - transcriptional co-factor and inhibits or induces transcrtiption factor activity

199
Q

What parts of the cell cycle does Rb have it’s main role in?

A

Regulates cell cycle by inhibiting the G1 to S phase transition

200
Q

What critical transcription factor does RB bind to and modulate the activity of

A

E2F

201
Q

How can RB induce cell cycle arrest

A

RB stabalizes the Cdk inhibitor p27

202
Q

RB inactivation causes promotion of ____ and _____ via increased expression of ______ target genes _____ and _____

A

chromosomal instability; angiogenesis; E2F; MAD2; VEGF

203
Q

p53 is a tumor suppressor gene or oncogene

A

tumor suppressor

204
Q

What happens to p53 in absence of cellular stress

A

Low levels of p53 induce antioxidant activity –> decreased ROS –> decreased DNA damage

205
Q

What activates p53?

A

DNA damage, oncogene activation, cell stress (hypoxia, nucleotide depletion)

206
Q

What are the downstream effects of p53 once activated?

A

transient or permanent cell cycle arrest, DNA repiar, apoptosis, inhibition of angiogenesis

207
Q

_____ is the critical biological function mediating the tumor suppressor function of p53

A

Apoptosis

208
Q

What is the main regulator of p53 & what type of molecule is it?

A

MDM2 - upiquitin ligase

209
Q

What signals DNA damage cause by ionizing radiation to p53?

A

ATM and Chk2 (protein kinases)

210
Q

What does phosphorylation of p53 cause?

A

Inability of MDM2 to bind to p53 (MDM2 can’t inactivate it)

211
Q

What signals cell stress to p53?

A

ATR and casein kinase II (both kinases)

212
Q

What oncogenes can induce p53 activity?

A

Ras

213
Q

How does Ras activate p53?

A

induces the activity of p14arf that sequesters MDM2 to the nucleolus of cells

214
Q

What is the central function of p53?

A

Cause either transient cell cycle arrest or senescence in response to DNA damage

215
Q

Transcriptional induction of _____ by p53 inhibits _____ and causes a pause in the _____ and _____ transitions of the cell cycle

A

p21 gene

several cyclin-cdk complexes

G1 to S and G2 to M

216
Q

What are the p53-inducible apoptotic target genes that work via the intrinsic pathway

A

Bax

NOXA

PUMA

p53/AIP1

217
Q

What are the p53-inducible apoptotic target genes that work via the extrinsic pathway?

A

FAS

IGF-BP3

DR5

PIDD

218
Q

_____, an inhibitor of angiogenesis is transcriptionally regulated by p53

A

Thrombospondin

219
Q

What tumor suppressor is nicknamed the guardian of the genome?

A

p53

220
Q

Phosphorylation of ____ results in a preference of p53 to induce pro-apoptotic genes

A

Ser46

221
Q

Oncogene activation is an upstream inducer of p53 that triggers _____

A

apoptosis

222
Q

What syndrome is characterized by a germline mutation of the p53 gene?

A

Li-Fraumeni syndrome

223
Q

Does p53 follow Knudson’s two hit hypothesis?

A

No - reduced amounts (haploinsufficiency) of p53 can cause transformation

224
Q

Unlike most tumor suppressor genes, some p53 mutation do not lead to _____

A

loss of function

225
Q

Viral proteins from human adenovirus, papilloma virus and SV40 inactivate ____ and ____ as a common oncogenic mechanism

A

p53 and RB

226
Q

What happens to a cell during apoptosis?

A

Shrinks, membrane blebs and buds, chromatin condenses and fragments precisely

227
Q

What molecule is central to both the intrinsic and extrinsic apoptotic pathways?

A

Caspases (proteases)

228
Q

What is the name caspase derived from?

A

cysteine-rich aspartate proteases

229
Q

What are two examples of death factors that activate the extrinsic apoptotic pathway?

A

Fas ligand

Tumor necrosis factor (TNF)

230
Q

What happens when ligands bind their death receptor?

A

Receptors undergo a conformational change –> heterodimers that tranduce the signal to the cell

231
Q

What does the conformation change in a death receptor expose?

A

Death domains on the cytoplasmic tail of the receptor

Ex: FADD (Fas-associated death domain protein) and TRADD (TNF receptor-associated death domain protein)

232
Q

Once the death domain binds and adaptor protein in the extrinsic apoptotic pathway, what happens?

A

Signal transduced to caspases - first = caspase-8

233
Q

What is the first caspase to be activated in the extrinsic pathway?

A

Caspase-8

234
Q

What is the term for the death ligands + receptors + adaptors + the initiating caspase in the extrinsic pathway?

A

death-inducing singaling complex (DISC)

235
Q

What are the executioner caspases in the extrinsic pathway?

A

Caspase 3, 6 and 7

236
Q

What are the target proteins in the extrinsic apoptotic pathway that breakdown the cell?

A

Nuclear lamins, cytoskeletal proteins (actin and intermediate filaments), kinases, DNase

237
Q

Cleavage of ______ is required for apoptosis induced by TNF

A

RB

238
Q

What triggers the intrinsic apoptotic pathway?

A

Stimuli from inside the cell - DNA damage, oxidative stress

239
Q

What family of proteins does the intrinsic apoptotic pathway work through?

A

Bcl-2 family

240
Q

Anti-apoptotic members of the Bcl-2 family

A

Bcl-2

Bcl-xL

Bcl-w

A1

Mcl-1

Boo

241
Q

Bax is a ____-apoptotic member of the Bcl-2 family

A

pro-

242
Q

Bok/Mtd is a ____-apoptotic member of the Bcl-2 family

A

-pro

243
Q

Bcl-x5 is a ____-apoptotic member of the Bcl-2 family

A

-pro

244
Q

Bak is a ____-apoptotic member of the Bcl-2 family

A

-pro

245
Q

Bcl-GL is a ____-apoptotic member of the Bcl-2 family

A

-pro

246
Q

Bad is a ____-apoptotic member of the Bcl-2 family

A

-pro

Also BH3-only

247
Q

Bik/Nbk/Blk is a ____-apoptotic member of the Bcl-2 family

A

pro-

Also BH3 only

248
Q

Bid is a ____-apoptotic member of the Bcl-2 family

A

-pro

Also BH3-only

249
Q

Hrk/DP5 is a ____-apoptotic member of the Bcl-2 family

A

-pro

Also BH3 only

250
Q

Bim/Bod is a ____-apoptotic member of the Bcl-2 family

A

-pro

Also, BH3 only

251
Q

Bmf is a ____-apoptotic member of the Bcl-2 family

A

Pro-

Also, BH3 only

252
Q

Noxa is a ____-apoptotic member of the Bcl-2 family

A

Pro-

Also BH3 only

253
Q

Puma/ Bbc3/BNIP3/BNIP3L is a ____-apoptotic member of the Bcl-2 family

A

Pro-

Also BH3-only

254
Q

Bcl-2 is a ____-apoptotic member of the Bcl-2 family

A

Anti-

255
Q

BclxL is a ____-apoptotic member of the Bcl-2 family

A

Anti-

256
Q

Bcl-w is a ____-apoptotic member of the Bcl-2 family

A
257
Q

A1 is a ____-apoptotic member of the Bcl-2 family

A

Anti-

258
Q

Boo is a ____-apoptotic member of the Bcl-2 family

A

Anti-

259
Q

Where are the apoptotic mediators stored for the intrinsic pathway?

A

Intermembrane space b/w the two mitochondrial membranes

260
Q

What is MOMP?

A

Mitochondrial outer membrane permeablilization - release of apoptotic mediators from the mitochondrial compartment

261
Q

When the intrinsic pathway is activated, which apoptotic factors are activated first?

A

BH3 only proteins - Bid and Bim

262
Q

What do Bim and Bid activate in the intrinsic apoptotic pathway?

A

Bax

263
Q

What does Bax do when it is activated in the intrinsic apoptotic pathway?

A

Transolcates from cytoplasm to outer mitochondrial membrane –> increases the permeability of the outer membrane

264
Q

What does Bcl-xL do?

A

Breaks apart Bax ogliomers

i.e. antiapoptotic

265
Q

What are released from the mitochondrial into the cytoplasm during the intrinsic apoptotic pathway

A

cytochrome C, pro-caspase-9

266
Q

What makes up the apoptosome in the cytoplasm of a cell

A

Cytochrome C, procaspase-9, dATP bound to Apaf-1

267
Q

What activates procaspase-9

A

Apaf-1 (protein co-factor)

268
Q

What is the first caspase activated in the intrinsic apoptotic pathway and what does it activate

A

Caspase-9 activates 3, 6 and 7

269
Q

What are IAPs?

A

inhibitors of apoptosis proteins

270
Q

Smac/DIABLO is a ____ and eliminates _____

A

Regulator of apoptosis released from mitochondria; eliminates inhibition of apoptosis by IAPs

271
Q

NF-kB is a potent promotor/inhibitor of apoptosis and induces the transcription of_____

A

inhibitor; IAPs

272
Q

XIAP directly binds to and inhibits the activity of ____ and ____

A

Caspase 3 and 7

273
Q

_____ and _____ compete for binding to XIAP

A

Smac/DIABLO and caspase-9

274
Q

Caspase-8 can activate ____ to also stimulate the intrinsic apoptotic pathway

A
275
Q

p53 plays a role in apoptosis in both the nucleus and cytoplasm. These functions are linked by ___

A

PUMA (p53 upregulated modulator of apoptosis

276
Q

Apoptotic signals stimulate ______ in normal cells while apopotitc signals stimulate _____ in cancer cells

A

Procaspase processing;

Cessation of IAP inhibition of processed caspases

277
Q

What are the TRAIL receptors?

A

Subfamily of TNF receptors (aka death receptors)

278
Q

What is TRAILR’s ligand?

A

TNF-related apoptosis-inducing ligand

279
Q

What does TRAIL do?

A

Stimulates apoptosis regarless of p53 gene profile in cancer cells but not most normal cells

280
Q

Alterations in the intrinsic/extrinisic apoptotic pathway are more common during carcinogenesis

A

intrinsic

281
Q

What is autophagy

A

recycling system for the cell - proteins and damage organelles targeted by lysosomes, cells reuse products of degradation

282
Q

Mitotic catastrophe is caused by ____

A

aberrant mitosis

283
Q

In the absence of Wnt, what complex is formed in the cell?

A

Degradation complex - axin + adenomatous polyposis coli (APC) protein + glycogen synthase kinase 3-beta (GSK3beta) + casein kinase I (CKI)

284
Q

Without Wnt, what transcriptional cofactor is phosphorylated by the degradation complex in the cell?

A

β-catenin (which is also ubiquitinated –> flags β- catenin for degredation by the proteasome

285
Q

When Wnt binds to the 7-pass transmembrane receptor ____ and co-receptor ______, a conformational change is induced and the co-receptor is phosphorylated by _____

A

Wnt binds frizzled + LRP —> cytoplasmic tail of LRP is phosphorylated by CKI

286
Q

When LRP is phosphorylated, what does it recruit and what is the result of this

A

recruits axin –> disrupts assembly of the degradation complex –> β catenin escapes degradation and moves to the nucleus

287
Q

What family of transcription factors does β-catenin act as a co-activator for?

A

Tcf/LEF family

288
Q

What are examples of target genes that Tcf/LEF transcription factors regulate

A

c-myc, cyclin D, genes that code for adhesion molecules from the ephrin (Eph_ receptor family

289
Q

Other than β-catenin, what other proteins are needed for activation of the target genes of the Tcf/LEF family of transcription factors

A

Bc19 (legless) and Pygopus

290
Q

Mutations that result in the constitutive activation of the Wnt pathway are responsible for 90% of what human cancer

A

colorectal cancer

291
Q

Loss of what tumor suppressor gene is considered the initiating event in most colorectal cancers in people and is sufficient to induce adenomas in mice?

A

APC

292
Q

The Hedgehog signaling pathway plays important roles in what processes

A

embyronic development, tissue self-renewal and carcinogenisis

Mainly inactive in adults

293
Q

What are the three members of the hedgehog proteins

A

Sonic, Desert and Indian

294
Q

What two transmembrane proteins are responsible for signal transduction from hedgehog

A

patched and smoothened

295
Q

In the absence of hedgehog, ____ is localized in the cilia and inhbitis ____ which prevents its localization to the cilia and supresses the pathway

A

patched localized in cilia, inhibits smoothened and prevents it from localizing to the cilia

296
Q

Without hedgehog, what is sequestered by a protein complex in the cytoplasm that induces its cleavage by proteasomes? What type of molecule is this?

A

Gli

Zinc finger transcritpion factor

297
Q

What does hedgehog bind to and what happens when it does

A

hedgehog binds patched –> smoothened relocates to the cilia and transduces a signal into the cell –> protein complex dissociates and releases Gli –> nucleus to regulate expression of hedgehog target genes

298
Q

What are examples of hedgehog target genes

A

Cyclin Ds, Bcl2, VEGF and Snail

299
Q

Patched is a (tumor suppressor/oncogene); patients with mutated patched have what syndrome

A

tumor suppressor; Gorlin syndrome (predisposed to skin, cerebellar and mm tumors)

300
Q

What group of proteins can repress the transcription of many developmental regulators and are therefore involved in maintenance (i.e. inducing and maintaing stem cell state) and repression of stem cells (including cancer stem cells)

A

polycomb group of proteins (PcG)

301
Q

Cyclopamine inhibits what pathway by inhibiting what transmembrane protein?

(fun fact - what plant does this come from and what does it do to sheep?)

A

inhibits hedgehog pathway by inhibiting the transmembrane protein smoothened

comes from wild corn lilies - teragoen that causes cyclopia in lambs (hence the name cyclopamine)

302
Q

What are the predominant extracellular matrix proteins that make up the basement membrane

A

laminins, type IV collagen and proteoglycans

303
Q

What are the major steps of metastasis?

A

Intravasation, transport, extravasation and metastatic colonization

304
Q

What are the characterizations of EMT

A
  • loss in cell polarity
  • deconstruction of epithelial cell-cell junctions
  • changes in cell shape
  • downregulation of epithelial markers (e-cadherin)
  • upregulation of mesenchymal proteins (N-cadherin)
  • secretion of specific proteases
  • increased cell protrustions and motility
305
Q

What signals from the tumor stroma induce EMT in neighboring tumor cells

A

hepatocyte growth factor (HGF) + MET receptor

EGF + EGFR

PDGF + PDGF-R

TGF-β + TGFR

All are receptors are TKRs

306
Q

What signal transduction pathways are activated in EMT

A

MAPK and PI3K

307
Q

What transcription factors are activated in EMT

A

Twist, Snail, slug, ZEB1, Goosecoid and FOXC2

308
Q

What does Snail do?

A

Transcription factor involved in EMT

binds E-box sequences in epithelial genes (ex: promoter region of E-cadherin promoter) and recruits polycomb repressor complex –> histone modifcation and epigenetic regulation to repress gene expression

309
Q

What type of proteins are cadherins?

A

calcium dependent transmembrane glycoproteins

310
Q

Who do cadherins interact with the cytoskeleton

A

via catenins

311
Q

What is the predominant cell adhesion molecule (CAM) in epithelial cells? Is it a tumor suppressor or promoter?

A

e-cadherin

tumor suppressor - secures cell-cell adhesion and suppresses metastasis

312
Q

What do integrins do?

A

mediate cell-ECM interactions and intracellular signal transduction

313
Q

After binding ligand, what doe integrins do?

A

cluster in the membrane and affect the cytoskeleton through interaction with acting-binding proteins and specific kinases (ex: focal adhesion kinase (FAK))

314
Q

What does focal adhesion kinase (FAK) do?

A

mediates cell motility through recruitment of Src and activation of the RAS pathway

315
Q

What is anoikis and how do intergrins play a role in it?

A

anoikis = apoptosis triggered in response to lack of ECM ligand binding and loss of cell adhesion

integrins w/o suitable ECM ligans recruit caspase-8 to membrane and trigger apoptosis

316
Q

What proteases are involved in EMT?

A

serine proteases and matrix metalloproteinases (MMPs)

317
Q

What do matrix metalloproteinases (MMPs) do?

A

cleave the extracellular domain of e-cadherin –> contribute to the loss of epithelial cell-cell junctions seen during emt

318
Q

What is the usual source of MMPs

A

Some tumor cells can synthesize MMPs but more often tumor cells induce surrounding stromal cells to make MMPs

319
Q

What protein can be upregulated on the membrane of tumor cells and induces production of MMPs in adjacent stromal cells?

A

extracellular matrix metalloproteinase inducer (EMMPRIN)

320
Q

What regulates the function of MMPs

A

endogenous tissue inhibitors (TIMPs)

321
Q

MMPs are what type of proteinase

A

zinc-dependent proteinases

322
Q

What steps are needed for a tumor cell to undergo intravasation?

A
  • attach to the stromal face of the vessel
  • degrade the vessel basement membrane (absent if invading lymphatics)
  • pass between endothelial cells (transendotheial migration)
323
Q

What are selectins and how do they play a role in EMT?

A

selectins = calcium dependent transmembrane receptors that mediate interactions with cancer cells by binding glycoprotein ligands expressed on adhering cells

role in attachment of cancer cells to endothelium (esp. E-selectin)

324
Q

What are disseminated tumor cells (DTCs)

A

cells that have spread but have not yet colonized

325
Q

What role do exosomes play in cancer metastasis

A

carry protein and nucleic acid - may help to prepare the premetastatic niche for cancer cells to colonize (bone marrow cells do this, too)

326
Q

What are examples of metastasis suppressor genes

A

NM23, mitogen-activated protein kinase kinase 4 (MKK4)

327
Q

What are examples of miRNA that suppress metastasis

A

miR-335 and miR-126

328
Q

What are Marimastat and Neovastat

A

metalloproteinase inhbitors (MPIs)

329
Q

What is cabozantinib (Cometriq)?

A

TKI that targets c-MET and VEGFR (approved for treatment of thyroid cancer in people)

330
Q

What are the anti-angiogenic factors

A

angiostatin, endostatin, prolactin, p53, thrombospondin-1 and -2

331
Q

What are the pro-angiogenic factors

A

VEGF

FGF

HGF (hepatocyte-derived GF)

EGF

PDGF

332
Q

What are the three families of endothelium-specific growth factors and their receptors

A
  1. VEGF/VEGFR
  2. angiopoietins and Tie receptors
  3. ephrins and ephrin receptors
333
Q

Which specific VEGF and receptor are responsible for the majority of angiogenic effects

A

VEGF-A + VEGFR-2

334
Q

Which VEGF and receptor play a role in the development of the lymphatic vascular system

A

VEGF-C + VEGFR-3

335
Q

What does VEGFR-1 do

A

Binds VEGF-A and restricts angiogenic response by VEGFR-2 (i.e. inhibitory)

336
Q

Plasminogen can be cleaved by _____ to release the angiogenic inhibitor ___-.

A

proteinases (including MMPs); releases angiostatin

337
Q

What is angiostatin’s endothelial cell surface receptor and what is the effect on angiogensis of it binding to its receptor

A

receptor = annexin II

effect: inhibits angiogenesis

338
Q

Endostatin is _____and is proteolytically released by _____

A

is a fragment of collagen XVIII;released by elastase and cathepsin

339
Q

What does endostatin do?

A

blockes MAPK activation in endothelial cells and blocks MMPs

340
Q

What is concomitant resistance?

A

primary tumor suppressing growth of dormant metastases

throught to be partly due to production of angiogenic inhibitors (angiostatin and endostatin) by primary tumors

341
Q

In areas of low oxygen concentration, angiogenesis is induced via ____

A

hypoxia-inducible factor-1α (HIF-1α)

342
Q

What regulates the activity of HIF?

A

Oxygen concentration - at normoxic levels (20%), HIF-1α is rapidly degraded (i.e. not regulated at level of mRNA expression)

343
Q

_____ is an important regulator of HIF-1α degradation

A

von Hippel-Lindau (VHL)

344
Q

What is the first step in targeting HIF-1α for degredation

A

under normoxic conditions, the enzyme prolyl 4-hydroxylase hydroxylates HIF-1α (enzyme directly binds and links molecular oxygen to specific proline residues on HIF-1α)

345
Q

_____ binds hydroxylated HIF-1α and adds ____

A

VHL; adds upiquitin –> targets it for proteosomal degradation

346
Q

Why is HIF-1α not hydroxylated under hypoxic conditions

A

4-hydroxylase is inactivated

347
Q

When HIF-1α is transported to the nucleus, what does it activate?

A

target genes via the hypoxia response element (HRE) - VEGF gene contains HRE in its promoter region

348
Q

What oncogenic proteins have been shown to upregulate VEGF

A

RTKs - EGFR

intracellular TKs - Src

Intracellular transduers - Ras

Transcription factors - Fos, Jun

349
Q

What is an example of a tumor suppressor gene that is involved in angiogensis? How do mutations in it cause angiogenesis to be favored?

A

p53

normally p53 activates the promoter for the angiogenic inhibitor thrombospondin-1 - mutations in p53 cause decreases in thrombospondin-1

350
Q

What enhances the signal from VEGFR-2 after it binds VEGF-A and what transduces it to the nucleus?

A

neuropilin-1 (Nrp1) enhances signal

MAPK cascade transduces it

351
Q

During angiogenesis, VEGFR-2 activation in the tip cells induces the expression and release of _____ which binds its receptor _____ on neighboring cells which is transported to the nucleus where it acts as a transcription factor to repress ____ and induce _____.

A

Delta-like 4 (DDL4) which binds the Notch receptor

represses VEGFR-2, induces VEGFR1

352
Q

When VEGFR-1 is activated, what is its effect

A

acts as a VEGF trap - reduces the amount of VEGF that can bind VEGFR2 –> growing BV sprout moves along the VEGF gradient

353
Q

What is vasculogenic mimicry?

A

tumor cells act as endothelial cells and form vascular-like structures

354
Q

what is vasculogenesis

A

differentiation and proliferation of endothelial cells from endothelial progenitor cells

355
Q

Are drugs that target angiogenesis (i.e. anti-angiogenic therapy) cytotoxic or cytostatic?

A

Cytostatic - require long-term continuous admin

356
Q

What is the recombinant humanized mAb that recognizes VEGF-A

A

bevacizumab (Avastin)

357
Q

What drug acts as a soluble decoy for VEGF by expressing both VEGFR-1 and -2

A

Aflibercept (VEGF-trap)

358
Q

What does Sorafenib (NExavar) target

A

TKI - VEGFR, PDGFR, FLT3, Kit and Raf

359
Q

What does Sunitinib target (SU-11248)

A

TKI: VEGFR, PDGFR, FLT3 and Kit

360
Q

T/F multiple drugs that directly targe HIF have been approved in human medicine

A

F - only durgs that indirectly target the HIF pathway have been approved (ex: bortezomib)

361
Q

Herceptin is a therapeutic Ab targeted against ____ and has shown to be antiangiogenic by ____

A

targets ErbB2

inhibits the production of angiogenic inducers (TGF-α and angiopoietin-1) and upregulates angiogenic inhibitors (thrombospondin)

362
Q

Depletion of ____ may contribute to tumor development by interfering with both nucleotide synthesis and DNA methylation

A

folate

363
Q

_____ upregulates the expression of nearly all of the core enzymes of glycolysis and inhibits the expression of some enzymes involved in the Krebs cycle and oxidative phosphorylation; this indicates it participates in what in cancer cells?

A

HIF-1α; Warburg effect

364
Q

The warburg effect describes what

A

increase in aerobic glycolysis that occurs in some tumor cells

365
Q

how does Tamoxifen work?

A

selective estrogen receptor modulator (SERM) - blocks estrogen binding to its receptor

366
Q

how do aromatase inhibitors work? what population of women with breast cancer may benefit most from these drugs?

A

inhbit the enzyme aromatase that converts androgens to estrogen

post-menopausal women - aromatase is their main source of estrogen

367
Q

What is an example of an aromatase inhibitor

A

Aromasin (exemestane)

368
Q

Most cancer cells do not epxress ____ and are therefore largely invisible to the immune system

A

B7 (aka CD86)

B7 is the ligand on the APC that interacts with CD28 on the T cell and is needed to activate the T cell

369
Q

Programmed death 1 protein (PD-1) binds to _____on APCs and _____ on many cell types including tumor cells

A

PD-L2 on APCs

PD-L1 on many cells

370
Q

Exposure to _____ produced by _____ induces PD-L1 expression on cells

A

IFNγ produced by activated T cells

371
Q

What does the PD-1 axis interfere with

A

Signaling mediated by the t-cell antigen receptor

372
Q

The interaction of PD-L1 on tumor cells and its receptor on activated effector T cells recruits ____ inactivates _____ blocking the production and secretion of molecules required for a cytotoxic response

A

recruits SHP-2 phosphatases, inactivates the PI3K cascade

373
Q

What are the phases of immunoediting?

A

Elimination of the cancer

Equilibrium - selection of less immunogenic tumor cells during an anti-tumor response

Escape - tumor evades the immune system

374
Q

What has a direct effect on CD4+ T cells (inhibits their proliferation and their production of cytokines)

A

IL-10

375
Q

What dendritic cell vaccine was made for treatment of prostate cancer?

A

Provenge (sipuleucel-T)

376
Q

What is the main disadvantage of dendritic cell vaccines?

A

labor-intensive and expensive

377
Q

What theapeutic checkpoint blockade is a fully human mAb against CTLA-4

A

ipilimumab

378
Q

CTLA-4 is what and is constitutively expressed on what cells?

A

protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells

379
Q

What does CTLA-4 bind to?

A

Binds to CD80 (B7) on T cells with more affinity and avidity than CD28 on APCs does

(CTLA-4 causes inhibitory signals to T cells, CD28 causes stimulation of T cells)

380
Q

Pembrolizumab (keytruda) targets what? What other drug also targets this?

A

PD-1

nivolumab (Opdivo)

381
Q

What two important oncogenes can induce inflammatory cytokines?

A

RAS and c-myc

382
Q

What are the key immune cells of chronic inflammatory responses

A

macrophages

383
Q

Many inflammatory pathways involved in carcinogenesis lead to the activation (via inflammatory cytokines) of _____

A

transcription factors STAT and NF-κB

384
Q

STAT is a transcription factor that promotes cell growth by _____ and increases survival by _____

A

induces the cyclin D, cyclin B and myc genes

increases survival by inducing anti-apoptotic genes such as Bcl-2

385
Q

How does NF-κB inhibit apoptosis?

A

induces anti-apoptotic gene expression (induction of Bcl-XL, cellular inhbitor of apoptosis (c-IAP) and cFLIP)

386
Q

NF-κB activates _____ and thus plays a role in regulating the cell cycle

A

cyclin D1 gene

Oncology Boards (26 decks)

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